Primary Mediastinal Large B-Cell Lymphoma (PMBL) Outcome May Be Significantly Improved by the Addition of Rituximab to Dose-Adjusted (DA)-EPOCH and Obviates the Need for Radiation: Results from a Prospective Study of 44 Patients.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 209-209 ◽  
Author(s):  
Kieron Dunleavy ◽  
Stefania Pittaluga ◽  
John Janik ◽  
Nicole Grant ◽  
Margaret Shovlin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
B Cell Lymphoma ◽  
Patient Characteristics ◽  
Salvage Chemotherapy ◽  
Molecular Signature ◽  
Rank Test ◽  
Bulky Disease ◽  
Prognostic Features

Abstract PMBL is a distinct clinicopathologic entity characterized by young age, female preponderance, localized disease, prominent sclerosis and CD30+. Gene expression profiling reveals a unique molecular signature, distinct from other DLBCL subtypes, with similarity to classical Hodgkin lymphoma (HL) (J Exp Med 198: 851, 2003). HL is typically CD20 negative whereas PMBL has robust CD20 staining. As with HL, the risk of local failure after anthracycline-based therapy in PMBL has led to routine mediastinal radiation. Given the young median age, female predominance and high cure rates, long-term toxicities from secondary malignancies and coronary artery disease can be life threatening. We prospectively evaluated the role of DA-EPOCH± R without routine radiation in 44 patients with untreated PMBL. The first 18 patients received DA-EPOCH alone and the subsequent 26 received DA-EPOCH+R. DA-EPOCH was administered for 6–8 cycles as described (Blood99: 2685, 2002). Most patients had adverse prognostic features with bulky disease, elevated LDH and extranodal sites, which were balanced among the 2 groups. Patient Characteristics Characteristics All Patients DA-EPOCH DA-EPOCH-R Total Patients 44 18 26 Gender (F/M) 26:18 (1.44) 10:8 (1.25) 19:9 (1.88) Median age, y (range) 34 (12–70) 34 (20–62) 34 (12–70) Median Mass cm (range) 9.8 (3–19.7) 8.4 (5.1–15.7) 10.2 (3–19.7) Bulky mass > 6 cm 34 (83%) 13 (87%) 21 (81%) ECOG PS > 1 4 (9%) 2 (11%) 2 (8%) Stage III or IV 19 (43%) 9 (50%) 10 (38%) LDH > Normal 32 (73%) 14 (78%) 18 (69%) Extranodal sites 25 (57%) 9 (50%) 16 (63%) Pleural effusion 15 (34%) 4 (22%) 11(42%) IHC profiling was similar in both groups and consistent with gene expression profiling of PMBL. Analysis of 40 cases showed CD20+ 40/40 (100%), CD10+ 2/30 (7%), BCL-6+ 21/26 (81%), MUM-1+ 10/24 (42%) and high MIB-1 with median (range) of 82% (54–98). At a median potential follow-up of 9.5 and 4.2 years, EFS and OS are shown below for DA-EPOCH and DA-EPOCH-R, respectively. Rituximab was associated with a significantly improved EFS (p=.038) and OS (p=0.023) by 2-tailed exact log-rank test with caveats associated with any non-randomized comparison. Three patients on DA-EPOCH-R had positive PET and biopsy after treatment. One received radiation (event), one recieved salvage chemotherapy and radiation (event), and one no further treatment after biopsy. DA-EPOCH-R is highly effective in PMBL with OS of 100% and obviated the need for radiation/surgery in 23/26 (88%) patients. Rituximab may significantly improve EFS and OS with DA-EPOCH-based treatment. Accrual continues. Figure Figure

Primary Mediastinal Large B-Cell Lymphoma (PMBL) Outcome Is Significantly Improved by the Addition of Rituximab to Dose Adjusted (DA)-EPOCH and Overcomes the Need for Radiation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 929-929 ◽  
Author(s):  
Kieron Dunleavy ◽  
Stefania Pittaluga ◽  
John Janik ◽  
Nicole Grant ◽  
Seth Steinberg ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
B Cell Lymphoma ◽  
Patient Characteristics ◽  
Rank Test ◽  
Tumor Proliferation ◽  
Grey Zone ◽  
Bulky Disease ◽  
Prognostic Features

Abstract Gene expression profiling has revealed that over one third of genes more highly expressed in PMBL than other DLBCLs are characteristically expressed in classical Hodgkin Lymphoma (HL) suggesting a biological relationship (J Exp Med198:851, 2003). PMBL and HL also share mediastinal presentation, young age, female predominance, prominent sclerosis and CD30 expression. Although some cases lie in a pathological “grey zone” between HL and PMBL, the latter is distinguished by robust CD20 expression. Like HL, local mediastinal failure after doxorubicin-based regimens has led to routine mediastinal xRT, which is associated with secondary malignancies and coronary disease. We analyzed the outcome of DA-EPOCH in 36 untreated PMBLs. No pts received xRT except for CNS PMBL. DA-EPOCH was administered with G-CSF for 2 cycles beyond CR for 6 to 8 cycles as described (Blood99:2685, 2002). The first 14 pts were on a DA-EPOCH study and the last 22 on a DA-EPOCH-Rituximab study. Most pts had adverse prognostic features with bulky disease, elevated LDH and extranodal sites, which were balanced among the 2 series. IHC in 34 cases was consistent with gene expression profiling of PMBL with frequent CD20+ 33/33 (100%), infrequent CD10+ 1/26 (4%) and variable BCL-6+ 17/24 (71%) and MUM-1+ 8/22 (36%) expression. Tumor proliferation by MIB-1 was high with a median (range) of 82% (54–98). IHC markers were similar among the 2 series. EFS and OS are shown below with a median follow-up of 8.6 and 3.4 yrs, respectively, for pts receiving DA-EPOCH −/+ R. Rituximab was associated with a significantly improved EFS (p=0.036) and trend in improved OS (p=0.10) by 2-tailed exact log-rank test. In conclusion, pt characteristics were consistent with the clinical-pathological and molecular definition of PMBL and prognostic features were similar to other series (Haematologica87:1258, 2002). These results suggest for the first time that rituximab significantly improves the outcome of PMBL and that DA-EPOCH-R obviates routine mediastinal xRT. DA-EPOCH-R may be more effective than CHOP-based treatment because it overcomes high tumor proliferation and employs pharmacodynamic dosing. Although needing confirmation, our results suggest DA-EPOCH-R without xRT is highly effective for PMBL. Patient Characteristics Patient Characteristics Characteristics All Patients DA-EPOCH DA-EPOCH-R Total Patients 36 14 22 Gender (F/M) 23/13 (1.77) 9/5 (1.8) 14/8 (1.75) Median age, y (range) 33 (12–70) 34 (20–62) 33 (12–70) Median Mass cm (range) 8.9 (3–16) 8.4 (5.1–15.7) 10 (3–16) Bulky mass > 6 cm 29 (83%) 11 (85%) 18 (82%) ECOG PS > 1 4 (11%) 2 (14%) 2 (9%) Stage III or IV 15 (42%) 7 (50%) 8 (36%) LDH > Normal 26 (72%) 12 (86%) 14 (64%) Extranodal sites 20 (56%) 7 (50%) 13 (59%) Pleural effusion 9 (25%) 3 (21%) 6 (27%) Figure Figure

Gene Expression Profiling Data in Lymphoma and Leukemia: Review of the Literature and Extrapolation of Pertinent Clinical Applications

2006 ◽  
Vol 130 (4) ◽  
pp. 483-520 ◽  
Author(s):  
Cherie H. Dunphy
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Gene Expression Profiling ◽  
Hodgkin Lymphoma ◽  
Expression Profiling ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
B Cell Lymphoma ◽  
Clinical Applications

Abstract Context.—Gene expression (GE) analyses using microarrays have become an important part of biomedical and clinical research in hematolymphoid malignancies. However, the methods are time-consuming and costly for routine clinical practice. Objectives.—To review the literature regarding GE data that may provide important information regarding pathogenesis and that may be extrapolated for use in diagnosing and prognosticating lymphomas and leukemias; to present GE findings in Hodgkin and non-Hodgkin lymphomas, acute leukemias, and chronic myeloid leukemia in detail; and to summarize the practical clinical applications in tables that are referenced throughout the text. Data Source.—PubMed was searched for pertinent literature from 1993 to 2005. Conclusions.—Gene expression profiling of lymphomas and leukemias aids in the diagnosis and prognostication of these diseases. The extrapolation of these findings to more timely, efficient, and cost-effective methods, such as flow cytometry and immunohistochemistry, results in better diagnostic tools to manage the diseases. Flow cytometric and immunohistochemical applications of the information gained from GE profiling assist in the management of chronic lymphocytic leukemia, other low-grade B-cell non-Hodgkin lymphomas and leukemias, diffuse large B-cell lymphoma, nodular lymphocyte–predominant Hodgkin lymphoma, and classic Hodgkin lymphoma. For practical clinical use, GE profiling of precursor B acute lymphoblastic leukemia, precursor T acute lymphoblastic leukemia, and acute myeloid leukemia has supported most of the information that has been obtained by cytogenetic and molecular studies (except for the identification of FLT3 mutations for molecular analysis), but extrapolation of the analyses leaves much to be gained based on the GE profiling data.

Cell-of-Origin in Diffuse Large B-Cell Lymphoma: Are the Assays Ready for the Clinic?

2015 ◽  
pp. e458-e466 ◽  
Author(s):  
David W. Scott
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Practical Implementation ◽  
Cell Of Origin ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma worldwide and consists of a heterogeneous group of cancers classified together on the basis of shared morphology, immunophenotype, and aggressive clinical behavior. It is now recognized that this malignancy comprises at least two distinct molecular subtypes identified by gene expression profiling: the activated B-cell-like (ABC) and the germinal center B-cell-like (GCB) groups—the cell-of-origin (COO) classification. These two groups have different genetic mutation landscapes, pathobiology, and outcomes following treatment. Evidence is accumulating that novel agents have selective activity in one or the other COO group, making COO a predictive biomarker. Thus, there is now a pressing need for accurate and robust methods to assign COO, to support clinical trials, and ultimately guide treatment decisions for patients. The “gold standard” methods for COO are based on gene expression profiling (GEP) of RNA from fresh frozen tissue using microarray technology, which is an impractical solution when formalin-fixed paraffin-embedded tissue (FFPET) biopsies are the standard diagnostic material. This review outlines the history of the COO classification before examining the practical implementation of COO assays applicable to FFPET biopsies. The immunohistochemistry (IHC)-based algorithms and gene expression–based assays suitable for the highly degraded RNA from FFPET are discussed. Finally, the technical and practical challenges that still need to be addressed are outlined before robust gene expression–based assays are used in the routine management of patients with DLBCL.

Gene-expression profiling and not immunophenotypic algorithms predicts prognosis in patients with diffuse large B-cell lymphoma treated with immunochemotherapy

Blood ◽  
2011 ◽  
Vol 117 (18) ◽  
pp. 4836-4843 ◽  
Author(s):  
Gonzalo Gutiérrez-García ◽  
Teresa Cardesa-Salzmann ◽  
Fina Climent ◽  
Eva González-Barca ◽  
Santiago Mercadal ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Tissue Microarrays ◽  
Prognostic Impact ◽  
Germinal Center B Cell ◽  
Large B Cell

Abstract Diffuse large B-cell lymphomas (DLBCLs) can be divided into germinal-center B cell–like (GCB) and activated-B cell–like (ABC) subtypes by gene-expression profiling (GEP), with the latter showing a poorer outcome. Although this classification can be mimicked by different immunostaining algorithms, their reliability is the object of controversy. We constructed tissue microarrays with samples of 157 DLBCL patients homogeneously treated with immunochemotherapy to apply the following algorithms: Colomo (MUM1/IRF4, CD10, and BCL6 antigens), Hans (CD10, BCL6, and MUM1/IRF4), Muris (CD10 and MUM1/IRF4 plus BCL2), Choi (GCET1, MUM1/IRF4, CD10, FOXP1, and BCL6), and Tally (CD10, GCET1, MUM1/IRF4, FOXP1, and LMO2). GEP information was available in 62 cases. The proportion of misclassified cases by immunohistochemistry compared with GEP was higher when defining the GCB subset: 41%, 48%, 30%, 60%, and 40% for Colomo, Hans, Muris, Choi, and Tally, respectively. Whereas the GEP groups showed significantly different 5-year progression-free survival (76% vs 31% for GCB and activated DLBCL) and overall survival (80% vs 45%), none of the immunostaining algorithms was able to retain the prognostic impact of the groups (GCB vs non-GCB). In conclusion, stratification based on immunostaining algorithms should be used with caution in guiding therapy, even in clinical trials.

scholarly journals Constitutive Nuclear Factor κB Activity Is Required for Survival of Activated B Cell–like Diffuse Large B Cell Lymphoma Cells

2001 ◽  
Vol 194 (12) ◽  
pp. 1861-1874 ◽  
Author(s):  
R. Eric Davis ◽  
Keith D. Brown ◽  
Ulrich Siebenlist ◽  
Louis M. Staudt
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Nuclear Factor ◽  
Large B Cell Lymphoma ◽  
Dlbcl Subtype ◽  
Large B Cell

Gene expression profiling has revealed that diffuse large B cell lymphoma (DLBCL) consists of at least two distinct diseases. Patients with one DLBCL subtype, termed activated B cell–like (ABC) DLBCL, have a distinctly inferior prognosis. An untapped potential of gene expression profiling is its ability to identify pathogenic signaling pathways in cancer that are amenable to therapeutic attack. The gene expression profiles of ABC DLBCLs were notable for the high expression of target genes of the nuclear factor (NF)-κB transcription factors, raising the possibility that constitutive activity of the NF-κB pathway may contribute to the poor prognosis of these patients. Two cell line models of ABC DLBCL had high nuclear NF-κB DNA binding activity, constitutive IκB kinase (IKK) activity, and rapid IκBα degradation that was not seen in cell lines representing the other DLBCL subtype, germinal center B-like (GCB) DLBCL. Retroviral transduction of a super-repressor form of IκBα or dominant negative forms of IKKβ was toxic to ABC DLBCL cells but not GCB DLBCL cells. DNA content analysis showed that NF-κB inhibition caused both cell death and G1-phase growth arrest. These findings establish the NF-κB pathway as a new molecular target for drug development in the most clinically intractable subtype of DLBCL and demonstrate that the two DLBCL subtypes defined by gene expression profiling utilize distinct pathogenetic mechanisms.

New Pathogenetic Insights Into Classical Hodgkin Lymphoma Revealed by Gene Expression Profiling of Microdissected Hodgkin/Reed-Sternberg Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 266-266 ◽  
Author(s):  
Enrico Tiacci ◽  
Verena Brune ◽  
Susan Eckerle ◽  
Wolfram Klapper ◽  
Ines Pfeil ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cells ◽  
B Cell ◽  
Gene Expression Profiling ◽  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Expression Profiling ◽  
Expression Profiles ◽  
B Cell Lymphoma ◽  
Cell Phenotype

Abstract Abstract 266 Background. Previous gene expression profiling studies on cHL have been performed on whole tissue sections (mainly reflecting the prominent reactive background in which the few HRS cells are embedded), or on cHL cell lines. However, cultured HRS cells do not likely reflect primary HRS cells in all aspects, being derived from end-stage patients and from sites (e.g. pleural effusions or bone marrow) which are not typically involved by cHL and where HRS cells lost their dependence on the inflammatory microenvironment of the lymph node. Methods. ∼1000–2000 neoplastic cells were laser-microdissected from hematoxylin/eosin-stained frozen sections of lymph nodes taken at disease onset from patients with cHL (n=16) or with various B-cell lymphomas (n=35), including primary mediastinal B-cell lymphoma (PMBL) and nodular lymphocyte-predominant Hodgkin lymphoma (nLPHL). After two rounds of in vitro linear amplification, mRNA was hybridized to Affymetrix HG-U133 Plus 2.0 chips. Expression profiles were likewise generated from sorted cHL cell lines and several normal mature B-cell populations. Results. Primary and cultured HRS cells, although sharing hallmark cHL signatures such as high NF-kB transcriptional activity and lost B-cell identity, showed considerable transcriptional divergence in chemokine/chemokine receptor activity, extracellular matrix remodeling and cell adhesion (all enriched in primary HRS cells), as well as in proliferation (enriched in cultured HRS cells). Unsupervised and supervised analyses indicated that microdissected HRS cells of cHL represent a transcriptionally unique lymphoma entity, overall closer to nLPHL than to PMBL but with differential behavior of the cHL histological subtypes, being HRS cells of the lymphocyte-rich and mixed-cellularity subtypes close to nLPHL cells while HRS cells of NS and LD exhibited greater similarity to PMBL cells. HRS cells downregulated a large number of genes involved in cell cycle checkpoints and in the maintenance of genomic integrity and chromosomal stability, while upregulating gene and gene signatures involved in various oncogenic signaling pathways and in cell phenotype reprogramming. Comparisons with normal B cells highlighted the lack of consistent transcriptional similarity of HRS cells to bulk germinal center (GC) B cells or plasma cells and, interestingly, a more pronounced resemblance to CD30+ GC B cells and CD30+ extrafollicular B cells, two previously uncharacterized subsets that are transcriptionally distinct from the other mature B-cell types. Conclusions. Gene expression profiling of primary HRS cells provided several new insights into the biology and pathogenesis of cHL, its relatedness to other lymphomas and normal B cells, and its enigmatic phenotype. Disclosures: No relevant conflicts of interest to declare.

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